Disposition of zofenopril calcium in healthy subjects.
Zofenopril calcium (1) is a prodrug that is hydrolyzed in vivo to the active angiotensin-converting enzyme (ACE) inhibitor SQ 26,333 (2). In a two-way crossover study, six healthy male subjects (age range 25-36 years) each received an iv 11.2-mg dose of [14C]SQ 26,703 (14C-3; the L-arginine salt of 2) and an oral 10-mg (equimolar) dose of 14C-1. After the iv dose of 14C-3, the 0-96-h recovery of radioactivity averaged 76 and 16% of the dose in urine and feces, respectively, indicating substantial biliary secretion. After the oral dose of 14C-1, excretion of radioactivity averaged 70% (urine) and 26% (feces). Negligible amounts of 1 were present in urine, indicating complete hydrolysis of the orally administered prodrug. The oral absorption of 1 was almost complete and the oral bioavailability of 2 averaged approximately 70%. The terminal elimination half-life for 2 after the iv dose averaged 5.5 h. Whole body clearance, renal clearance, nonrenal clearance, and Vdss averaged 11.4, 3.1, and 8.3 mL/min/kg and 1.3 L/kg, respectively. These data indicated that 2 is eliminated by the kidney as well as the liver, is extensively metabolized, and is distributed extensively into extravascular sites.
Singhvi
S M
SM
Department of Drug Metabolism, Squibb Institute for Medical Research, Princeton, NJ.
Foley
J E
JE
Willard
D A
DA
Morrison
R A
RA
D000284:Administration, Oral; D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D002216:Captopril / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002855:Chromatography, Thin Layer; D005033:Ethylmaleimide / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D011485:Protein Binding; D011897:Random Allocation; D012016:Reference Values
D000806:Angiotensin-Converting Enzyme Inhibitors; D001798:Blood Proteins; C044958:zofenopril; D002216:Captopril; D005033:Ethylmaleimide